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Background: Hemodynamic impairment of blood pressure may play a crucial role in determining the mechanisms of stroke in symptomatic intracranial atherosclerotic stenosis). We aimed to elucidate this issue and assess the impacts of modifications to blood pressure on hemodynamic impairment., Methods: From the Third China National Stroke Registry III, computed fluid dynamics modeling was performed using the Newton-Krylov-Schwarz method in 339 patients with symptomatic intracranial atherosclerotic stenosis during 2015 to 2018. The major exposures were translesional systolic blood pressure (SBP) drop and poststenotic mean arterial pressure (MAP), and the major study outcomes were cortex-involved infarcts and borderzone-involved infarcts, respectively. Multivariate logistic regression models and the bootstrap resampling method were utilized, adjusting for demographics and medical histories., Results: In all, 184 (54.3%) cortex-involved infarcts and 70 (20.6%) borderzone-involved infarcts were identified. In multivariate logistic model, the upper quartile of SBP drop correlated with increased cortex-involved infarcts (odds ratio, 1.92 [95% CI, 1.03-3.57]; bootstrap analysis odds ratio, 2.07 [95% CI, 1.09-3.93]), and the lower quartile of poststenotic MAP may correlate with increased borderzone-involved infarcts (odds ratio, 2.07 [95% CI, 0.95-4.51]; bootstrap analysis odds ratio, 2.38 [95% CI, 1.04-5.45]). Restricted cubic spline analysis revealed a consistent upward trajectory of the relationship between translesional SBP drop and cortex-involved infarcts, while a downward trajectory between poststenotic MAP and borderzone-involved infarcts. SBP drop correlated with poststenotic MAP negatively (r s =-0.765; P <0.001). In generating hemodynamic impairment, simulating blood pressure modifications suggested that ensuring adequate blood pressure to maintain sufficient poststenotic MAP appears preferable to the reverse approach, due to the prolonged plateau period in the association between the translesional SBP drop and cortex-involved infarcts and the relatively short plateau period characterizing the correlation between poststenotic MAP and borderzone-involved infarcts., Conclusions: This research elucidates the role of hemodynamic impairment of blood pressure in symptomatic intracranial atherosclerotic stenosis-related stroke mechanisms, underscoring the necessity to conduct hemodynamic assessments when managing blood pressure in symptomatic intracranial atherosclerotic stenosis., Competing Interests: Disclosures None.

Cerebral collateral circulation (CC) is associated with the recurrence and severity of acute ischemic stroke (AIS), and early identification of poor CC is helpful for the prevention of AIS. In this study we evaluated the association between serum albumin levels and CC in AIS using logistic regression. Propensity score (PS) matching was used to eliminate the effect of confounders, and restricted cubic splines (RCS) were employed to explore potential nonlinear associations between albumin and CC. In unadjusted logistic regression analysis, lower albumin (OR = 0.85, 95% CI = 0.79-0.92) was associated with poor CC, and after adjusting for covariates, the odds of lower albumin for poor CC compared to good CC were 0.86 (95% CI = 0.79-0.94). In the PS cohort, the association of albumin with CC was consistent with those of the original cohort. RCS results showed a linear relationship between albumin and CC (P values of .006 and .08 for overall and nonlinear associations, respectively). The results of this study suggest that lower serum albumin is independently associated with an increased risk of poor CC, which may serve as an effective predictive indicator for poor CC in patients with severe intracranial atherosclerotic stenosis., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Purpose: While prior studies identified risk factors for recurrent stroke in patients with symptomatic intracranial atherosclerotic disease, few have assessed risk factors for early infarct recurrence., Methods: We performed a post hoc analysis of the MYRIAD study (Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease) of intracranial atherosclerotic disease patients with recent (<21 days) stroke/transient ischemic attack, 50% to 99% stenosis and who underwent 6- to 8-week magnetic resonance imaging (MRI) per protocol. Infarct recurrence was defined as new infarcts in the territory of the symptomatic artery on brain MRI at 6 to 8 weeks compared to index brain MRI. Qualifying events and clinical and imaging outcomes were centrally ascertained by 2 independent reviewers. We assessed the association between baseline clinical and imaging variables and recurrent infarct in bivariate models and multivariable logistic regression to identify independent predictors of infarct recurrence., Results: Of 105 enrolled patients in MYRIAD, 89 (84.8%) were included in this analysis (mean age, 64±12 years, 54 [60.7%] were male, and 53 [59.6%] were White). The median time from qualifying event to MRI was 51+16 days, on which 22 (24.7%) patients had new or recurrent infarcts. Younger age (57.7 versus 66.0 years; P <0.01), diabetes (32.6% versus 14.6%, P =0.05), index stroke (31.3% versus 4.6%, P =0.01), anterior circulation location of stenosis (29.7% versus 12.0%, P =0.08), number of diffusion-weighted imaging lesions (>1: 40.0%, 1: 26.9% versus 0: 4.4%, P <0.01), and borderzone infarct pattern (63.6% versus 25.0%, P =0.01) on baseline MRI were associated with new or recurrent infarcts. Age (adjusted odds ratio, 0.93 [95% CI, 0.89-0.98], P <0.01) and number of diffusion-weighted imaging lesions (adjusted odds ratio, 3.24 [95% CI, 1.36-7.71], P <0.01) were independently associated with recurrent infarct adjusting for hypertension, diabetes, and stenosis location (anterior versus posterior circulation)., Conclusions: An index multi-infarct pattern is associated with early recurrent infarcts, a finding that might be explained by plaque instability and artery-to-artery embolism. Further investigation of plaque vulnerability in intracranial atherosclerotic disease is needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02121028.

Abstract: Atherosclerosis remains a leading cause of morbidity and mortality, with revascularization remaining a cornerstone of management. Conventional revascularization modalities remain challenged by target vessel reocclusion-an event driven by mechanical, thrombotic, and proliferative processes. Despite considerable advancements, restenosis remains the focus of ongoing research. Adjunctive agents, including dipyridamole, offer a multitude of effects that may improve vascular homeostasis. We sought to quantify the potential therapeutic impact of dipyridamole on vascular occlusion. We performed a literature search (EMBASE and MEDLINE) examining studies that encompassed 3 areas: (1) one of the designated medical therapies applied in (2) the setting of a vascular intervention with (3) an outcome including vascular occlusion rates and/or quantification of neointimal proliferation/restenosis. The primary outcome was vascular occlusion rates. The secondary outcome was the degree of restenosis by neointimal quantification. Both human and animal studies were included in this translational analysis. There were 6,839 articles screened, from which 73 studies were included, encompassing 16,146 vessels followed up for a mean of 327.3 days (range 7-3650 days). Preclinical studies demonstrate that dipyridamole results in reduced vascular occlusion rates {24.9% vs. 48.8%, risk ratio 0.53 [95% confidence interval (CI) 0.40-0.70], I2 = 39%, P < 0.00001}, owing to diminished neointimal proliferation [standardized mean differences -1.13 (95% CI -1.74 to -0.53), I2 = 91%, P = 0.0002]. Clinical studies similarly demonstrated reduced occlusion rates with dipyridamole therapy [23.5% vs. 31.0%, risk ratio 0.77 (95% CI 0.67-0.88), I2 = 84%, P < 0.0001]. Dipyridamole may improve post-intervention vascular patency and mitigate restenosis. Dedicated studies are warranted to delineate its role as an adjunctive agent after revascularization., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: The role of regional hypoperfusion as a contributor to stroke risk in atherosclerotic vertebrobasilar disease has recently been confirmed by the observational VERiTAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) Study. We examined the stability of hemodynamic status over time and its relationship to stroke risk in patients from this prospective cohort., Methods: VERiTAS enrolled patients with recently symptomatic ≥50% atherosclerotic stenosis/occlusion of vertebral and/or basilar arteries. Large vessel flow in the vertebrobasilar territory was assessed using quantitative magnetic resonance angiography, and patients were designated as low or normal flow based on distal territory regional flow, incorporating collateral capacity. Patients underwent standard medical management and follow-up for primary outcome event of vertebrobasilar territory stroke. Quantitative magnetic resonance angiography imaging was repeated at 6, 12, and 24 months. Flow status over time was examined relative to baseline and relative to subsequent stroke risk using a cause-specific proportional hazard model, with flow status treated as a time-varying covariate. Mean blood pressure was examined to assess for association with changes in flow status., Results: Over 19±8 months of follow-up, 132 follow-up quantitative magnetic resonance angiography studies were performed in 58 of the 72 enrolled patients. Of the 13 patients with serial imaging who had low flow at baseline, 7 (54%) had improvement to normal flow at the last follow-up. Of the 45 patients who had normal flow at baseline, 3 (7%) converted to low flow at the last follow-up. The mean blood pressure did not differ in patients with or without changes in flow status. The time-varying flow status remained a strong predictor of subsequent stroke (hazard ratio, 10.3 [95% CI, 2.2-48.7])., Conclusions: There is potential both for improvement and worsening of hemodynamics in patients with atherosclerotic vertebrobasilar disease. Flow status, both at baseline and over time, is a risk factor for subsequent stroke, thus serving as an important prognostic marker. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00590980.

Background and Purpose: Understanding the mechanisms underlying progression/regression of symptomatic intracranial atherosclerotic stenosis (sICAS) will inform secondary prevention of the patients. Focal wall shear stress (WSS) may play an important role, which, however, had seldom been investigated., Methods: Patients with acute ischemic stroke or transient ischemic attack (TIA) attributed to 50% to 99% intracranial atherosclerotic stenosis were recruited. All patients underwent cerebral computed tomography angiography at baseline, and a computational fluid dynamics model was built based on computed tomography angiography to simulate blood flow and quantify WSS in the vicinity of the sICAS lesion. All patients received optimal medical treatment and a second computed tomography angiography at 1 year. The change in the luminal stenosis from baseline to 1 year in sICAS was defined as progression (increased >10%), quiescence (±10%), or regression (decreased >10%). Associations between baseline WSS metrics and sICAS regression were analyzed., Results: Among 39 patients (median age 62 years; 27 males), sICAS luminal stenosis progressed, remained quiescent and regressed in 6 (15.4%), 15 (38.5%), and 18 (46.2%) cases, respectively. A higher maximum WSS and larger high-WSS area, throughout the sICAS lesion or obtained separately in the proximal and distal parts of the lesion, were independently associated with regression of luminal stenosis in sICAS over 1 year., Conclusions: A majority of sICAS lesions regress or stay quiescent in the luminal stenosis over 1 year after stroke under optimal medical treatment, when higher focal WSS may facilitate stenosis regression. Further studies of the effects of hemodynamics including WSS in altering plaque vulnerability and stroke risks are needed.

Background and Purpose- There is debate over an optimal systolic blood pressure (SBP) in secondary stroke prevention of patients with symptomatic intracranial atherosclerotic stenosis (sICAS). We investigated whether translesional pressure gradient across sICAS would alter the relationship between SBP and risk of recurrent stroke in such patients. Methods- We recruited patients with sICAS (50%-99% stenosis) confirmed in computed tomography angiography. We simulated blood flow across sICAS with computed tomography angiography-based computational fluid dynamics models. Translesional pressure ratio (PR=Pressure post-stenotic /Pressure pre-stenotic ) was calculated in each case. Pressure ratio (PR) ≤ median was defined as low PR, indicating larger translesional pressure gradient across sICAS. All patients received optimal medical treatment. We investigated the interaction of translesional PR and mean SBP during follow-up (SBP FU ) in determining the risk of the primary outcome, recurrent ischemic stroke in the same territory within 1 year. Results- Among 157 patients with sICAS, the median PR was 0.93. Multivariate Cox regression revealed significant PR-SBP FU interaction on the primary outcome ( P =0.008): in patients with normal PR, risk of primary outcome significantly decreased with lower SBP FU (hazard ratio for 10 mm Hg decrement =0.46; P =0.018); however, in those with low PR, SBP FU ≤130 mm Hg was associated with significantly increased risk of primary outcome, compared with 130FU <150 mm Hg (hazard ratio=5.08; P =0.043). Conclusions- Low SBP level may be associated with increased risk of stroke recurrence in patients with sICAS with a large translesional pressure gradient. Translesional PR by computational fluid dynamics models may yield a promising indicator to guide more individualized blood pressure management in patients with sICAS, warranting future studies.

Background and Purpose: The presence of intracranial artery calcification is associated with an increased risk for stroke. However, calcified atherosclerotic plaques are also known to be less vulnerable to rupture. Given this discrepancy, we investigated whether the vulnerability of intracranial arterial atherosclerosis differed based on the presence or absence of calcification., Methods: We considered consecutive patients with acute stroke in the unilateral middle cerebral artery (MCA) territory. Patients with any stenotic MCAs were included in this study. Symptomatic MCA was defined as the occurrence of infarctions relevant to the stenotic MCA. The presence of calcification in the MCA was evaluated on noncontrast thin-section computed tomography images using a 3dimensional software package. Generalized estimating equations were used to compare the frequency of calcification between symptomatic and asymptomatic stenosis., Results: Of the 1066 MCAs examined in 533 patients, 645 MCAs were stenotic and were included in the study. Among the 645 stenotic MCAs, 406 MCAs (62.9%) were symptomatic. Calcification was observed in 36 MCAs (5.6%). Calcification in the MCA was more frequently observed in the asymptomatic group (7.9% versus 4.2%; P =0.032). On multivariable analysis, the presence of calcification in MCA atherosclerosis was less frequent in the symptomatic group (odds ratio, 0.46; 95% confidence interval, 0.23-0.92; P =0.027)., Conclusions: This study showed that calcified atherosclerosis in the MCA was less frequently symptomatic., (© 2017 American Heart Association, Inc.)

Background and Purpose: Tandem steno-occlusive lesions were poorly represented in randomized trials and represent a major challenge for endovascular thrombectomy in acute anterior circulation strokes. The impact of the cervical carotid lesion cause (ie, atherosclerotic versus dissection) on outcome of tandem patients endovascularly treated remains to be assessed., Methods: We retrospectively analyzed individual data of prospectively collected consecutive tandem patients treated with endovascular thrombectomy. The primary outcome was favorable outcome at 90 days (modified Rankin Scale score of 0-2). Secondary efficacy outcomes included successful reperfusion (modified Thrombolysis in Cerebrovascular Infarction scores of 2b-3), time to reperfusion, and safety outcomes encompassed procedural complications, symptomatic intracerebral hemorrhage, and 90-day mortality., Results: Among the 295 included patients, 65 had cervical carotid dissection and 230 had cervical carotid atherosclerotic cause. The rate of favorable outcome was 56.3% in the dissection group versus 47.6% in the atherosclerotic arm (center-, age-, and admission National Institutes of Health Stroke Scale-adjusted odds ratio, 1.08; 95% confidence interval, 0.50-2.30; P =0.85). No significant differences were observed in secondary outcomes. The rates of successful reperfusion, symptomatic intracerebral hemorrhage, and 90-day mortality were 78.5% versus 74.5% ( P =0.13), 4.6% versus 5.2% ( P =1.0), and 7.8% versus 15.3% ( P =0.94) in the dissection versus atherosclerotic groups, respectively. The median procedural time was 76 minutes (interquartile range, 52-95 minutes) in the dissection group and 67 minutes (interquartile range, 45-98 minutes) in the atherosclerotic group ( P =0.24)., Conclusions: We found no differences in the outcomes of patients with anterior circulation tandem atherosclerotic and dissection lesions treated with endovascular thrombectomy. Further studies are warranted., (© 2017 American Heart Association, Inc.)

Rationale: Intracranial vascular atherosclerotic occlusion is one of the most common causes of ischemic stroke world wide. The involvement of large intracranial vessels, in particular, the middle cerebral artery, is usually associated with unfavorable outcomes in patients. Spontaneous recanalization of atherosclerotic occlusion is relatively rare., Patient Concerns: The first patient was a 43-year-old male with slurred speech and left-sided weakness for a duration of 24 hours. The second was a 59-year-old male with left-sided weakness over a period of 13 hours. The last was a 49-year-old female patient presented with a 1-month history of right-sided headache., Diagnoses: Atherosclerotic middle cerebral artery occlusion., Interventions: In all cases, oral aspirin (100 mg; once daily), Plavix (75 mg; once daily), and Lipitor (40 mg; once daily) were used . Oral Plavix was stopped 3 months., Outcomes: Spontaneous recanalization occured in the three cases of atherosclerotic middle cerebral artery occlusion., Lessons: Spontaneous recanalization may occur in both early and late stages of atherosclerotic middle cerebral artery occlusion. Clinicians should be aware of this particular condition, as it may represent a relatively favorable prognosis.

Background: Blood pressure (BP) variability has been shown to be an independent risk factor of stroke and target organ damage because of hypertension, but so far, there have been very few studies investigating the impact of BP variability on cerebrovascular atherosclerosis., Methods: A total of 409 participants were enrolled and classified according to patterns of cerebrovascular atherosclerosis (i.e. large or small artery atherosclerosis; extracranial; or intracranial artery atherosclerosis). Coefficient of variation (CV) was used as a marker of BP variability. Multivariate binary logistical regression was used to analyze the associations between BP variability and the risk of different patterns of cerebrovascular atherosclerosis., Results: The risk of large artery atherosclerosis and extracranial arterial stenosis, respectively, had a dose-responsive positive relationship with the tertiles of awake systolic blood pressure (SBP) CVs [large artery atherosclerosis, the second tertile, adjusted odds ratio (OR)=2.839, 95% confidence interval (CI) 1.593-5.059, P<0.001; the third tertile, adjusted OR=4.010, 95% CI 1.859-8.651, P<0.001; extracranial arterial stenosis, the second tertile, adjusted OR=2.274, 95% CI 1.189-4.348, P=0.013; the third tertile, adjusted OR=2.568, 95% CI 1.230-5.360, P=0.012, when referenced to the first tertile], but not with those of mean awake SBP. The third tertile of awake SBP CVs indicated a significantly higher risk of intracranial arterial stenosis (adjusted OR=2.253, 95% CI 1.118-4.538, P=0.023) and advanced intracranial arterial stenosis (adjusted OR=5.073, 95% CI 2.064-12.466, P<0.001) when referenced to the first tertile., Conclusion: In Chinese patients with acute atherosclerotic stroke, higher awake BP variability (measured in the subacute stage) might be associated with a higher risk of large artery atherosclerosis.

Background and Purpose: Acute intracranial occlusion can be associated with in situ thrombo-occlusion in relation to preexisting intracranial atherosclerotic disease. We aimed to assess residual stenosis at the site of a target arterial lesion (TAL) to determine whether residual stenosis at the TAL is associated with underlying intracranial atherosclerotic disease., Methods: One hundred and sixty-three patients who underwent endovascular therapy for M1 middle cerebral artery occlusion and achieved angiographic reperfusion were selected for analysis. The presence of residual stenosis at the TAL was classified using the Arterial Occlusive Lesion (AOL) scale at postprocedural angiography, and the severity of stenosis was grouped into none, mild (<50%), moderate (50%-69%), severe (70%-99%), and occlusion on postprocedural and follow-up angiography. We also recorded the incidence of instant reocclusion occurring during the procedure and delayed reocclusion detected on follow-up angiography., Results: Seventy-four patients (45.5%) showed target arterial residual stenosis (AOL 2). As to the TAL pathogenesis, 40 patients were classified into in situ thrombo-occlusion (54.1% of AOL 2 and 24.5% of M1 occlusion). The occurrence of instant or delayed reocclusion was independently associated with a low chance of favorable 3-month outcome. Furthermore, the occurrence of delayed reocclusion was associated with excellent pretreatment collateral flow and early neurological worsening, but not the severity of residual stenosis at the TAL., Conclusions: In population with a high prevalence of intracranial atherosclerotic disease, residual stenosis may be attributed to in situ thrombo-occlusion with underlying intracranial atherosclerotic disease in ≈25% of cases, hindering functional recovery via the occurrence of instant or delayed reocclusion., (© 2016 American Heart Association, Inc.)

The aim of the study was to assess the capacity of dynamic cerebral autoregulation (dCA) in asymptomatic patients with unilateral middle cerebral artery (MCA) stenosis.Fifty-seven patients with asymptomatic mild, moderate, and severe unilateral MCA stenosis and 8 patients with symptomatic severe unilateral MCA stenosis diagnosed by transcranial Doppler were enrolled. Twenty-four healthy volunteers served as controls. The noninvasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously from each subject in the supine position. Transfer function analysis was applied to determine the autoregulatory parameters (phase difference [PD] and gain).The PD values in the severe stenosis groups were significantly lower than those of the control group (60.71 ± 18.63°), the asymptomatic severe stenosis group was impaired ipsilaterally (28.94 ± 27.43°, P < 0.001), and the symptomatic severe stenosis group was impaired bilaterally (13.74 ± 19.21°, P < 0.001; 19.68 ± 14.50°, P = 0.006, respectively). The PD values in the mild and moderate stenosis groups were not significantly different than the controls (44.49 ± 27.93°; 48.65 ± 25.49°, respectively). The gain values in the mild and moderate groups were higher than in the controls (1.00 ± 0.58 cm/s/mm Hg vs 0.86 ± 0.34 cm/s/mm Hg, and 1.20 ± 0.59 cm/s/mm Hg vs 0.86 ± 0.34 cm/s/mm Hg, respectively). The gain values in the severe stenosis groups were significantly lower than that in the control group: the asymptomatic severe stenosis group was lower bilaterally (0.56 ± 0.32 cm/s/mm Hg, P = 0.003; 0.60 ± 0.32 cm/s/mm Hg, P < 0.05, respectively), whereas the symptomatic severe group was lower unilaterally (on the contralateral side) (0.53 ± 0.43 cm/s/mm Hg, P < 0.05).In asymptomatic patients with unilateral MCA stenosis, only the dCA of the severe stenosis was ipsilaterally impaired. Acute stroke may aggravate the impaired dCA and even spread contralaterally., Competing Interests: The authors have no funding and conflicts of interest to disclose.

Background and Purpose: Intracranial atherosclerotic stroke (ICAS) has various stroke mechanisms, including branch occlusive disease (BOD), subcortical infarcts caused by parent arterial disease occluding the perforator's orifice, and non-BOD, infarcts beyond the subcortical area caused by artery-to-artery embolism. To test whether these 2 types of ICAS had different vascular pathophysiologies, we compared the high-resolution magnetic resonance imaging characteristics between BOD and non-BOD ICAS., Methods: Eighty patients with acute infarcts caused by ICAS of proximal middle cerebral artery or basilar artery without carotid/cardiac embolic sources or nonatherosclerotic causes were enrolled (36 BOD and 44 non-BOD patients). The steno-occlusive intracranial artery at the maximal stenosis was analyzed for vascular remodeling and wall enhancement., Results: BOD had distinct radiological features in terms of vascular morphology and enhancement. BOD showed a milder stenosis than non-BOD (P<0.001). Positive remodeling was more frequently observed in non-BOD than in BOD (P=0.005). Wall area index was also lower in BOD. Plaque enhancement was observed in all but one non-BOD patient and in one fourth of BOD patients (P=0.003). Although both types showed an eccentric enhancement, this enhancement was more frequently distributed in the BOD group on the side where the perforators arose. As the number of asymptomatic intracranial stenosis increased, the degree of stenosis (rho=0.513, P=0.003) increased in the BOD group, whereas enhanced plaque area (rho=0.343, P=0.030) increased in the non-BOD group., Conclusions: Our data indicate that BOD is a common and unique form of ICAS, distinct from non-BOD. These 2 types of ICAS have different vascular pathophysiologies in terms of vascular remodeling and plaque characteristics., (© 2015 American Heart Association, Inc.)

Background and Purpose: Diagnosis of intracranial artery atherosclerosis remains often uncertain. The high-resolution magnetic resonance imaging (HR-MRI) enables vessel wall assessment for more precise diagnoses. The aim of the present study was to investigate the etiologies of middle cerebral artery steno-occlusive disease in young adult patients with few atherosclerotic risk factors using HR-MRI., Methods: We prospectively studied patients who visited a tertiary hospital in Seoul, Korea, and had (1) unilateral middle cerebral artery disease (≥50% stenosis or occlusion), (2) were ≤55 years old and had no or minimal (≤1) atherosclerotic risk factors. We excluded patients with a confirmed diagnosis of Moyamoya disease, vasculitis, or dissection and those having emboligenic sources. A presumptive diagnosis was made based on HR-MRI findings, and patients were categorized as HR-athero (atherosclerotic disease), HR-MMD (Moyamoya disease), HR-dissection, or HR-vasculitis., Results: Among 95 patients analyzed, 26 (27.4%) had HR-athero who were more often male (P=0.004), smokers (P=0.018), and had focal stenosis (P=0.003) than others.As compared with the HR-athero patients, 29 HR-MMD patients were more often female (P<0.001) and more often had occlusive lesions (P=0.001) and nonfocal stenosis (P<0.001). The 22 HR-dissection patients tended to have hypertension less often, and the 13 HR-vasculitis patients were younger (P=0.004) and tended to have nonfocal stenosis. [corrected]., Conclusions: In our cohort of young patients with minimal risk factors, atherosclerosis seems to be an uncommon pathology of middle cerebral artery stenosis. HR-MRI aids us to make a more reliable diagnosis., (© 2015 American Heart Association, Inc.)

Background and Purpose: Diabetes mellitus is an independent risk factor for lacunar strokes. Few data are available regarding patient features, infarct location, and recurrent vascular events for patients with diabetes mellitus with lacunar stroke., Methods: We compared features at study entry and prognosis during 3.6 years of follow-up of patients with diabetes mellitus versus patients without diabetes mellitus with recent lacunar stroke participating in the Secondary Prevention of Small Subcortical Strokes (SPS3) randomized trial., Results: Among the 3020 participants, the prevalence of diabetes mellitus was 37% with a mean duration of 11 years. Diabetes mellitus was independently associated with slightly younger age (63 versus 64 years; P<0.001), Hispanic ethnicity (36% versus 28%; P<0.0001), ischemic heart disease (11% versus 6%; P=0.002), and peripheral vascular disease (5% versus 2%; P<0.001). Patients with diabetes mellitus more frequently had intracranial stenosis ≥50% (P<0.001), infarcts involving the brain stem or cerebellum (P<0.001), and more extensive white matter abnormalities (P<0.001). Patients with diabetes mellitus were almost twice as likely to have a recurrent stroke (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.4-2.3), recurrent ischemic stroke (HR, 1.8; 95% CI, 1.4-2.4), disabling/fatal stroke (HR, 1.8; 95% CI, 1.2-2.9), myocardial infarction (HR, 1.7; 95% CI, 1.0-2.8), and death (HR, 2.1 95% CI, 1.6-2.8) compared with patients without diabetes mellitus., Conclusions: Patients with diabetes mellitus with lacunar stroke have a distinctive clinical profile that includes double the prevalence of systemic and intracranial atherosclerosis, preferential involvement of the posterior circulation, and a poor prognosis for recurrent stroke and death., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00059306., (© 2014 American Heart Association, Inc.)

Background and Purpose: A promising method for identifying hemodynamic impairment that may serve as a biomarker for stroke risk in patients with intracranial stenosis is cerebrovascular reactivity (CVR) mapping using noninvasive MRI. Here, abilities to measure CVR safely in the clinic using hypercarbic hyperoxic (carbogen) gas challenges, which increase oxygen delivery to tissue, are investigated., Methods: In sequence with structural and angiographic imaging, blood oxygenation level-dependent carbogen-induced CVR scans were performed in patients with symptomatic intracranial stenosis (n=92) and control (n=10) volunteers, with a subgroup of patients (n=57) undergoing cerebral blood flow-weighted pseudocontinuous arterial spin labeling CVR. Subjects were stratified for 4 substudies to evaluate relationships between (1) carbogen and hypercarbic normoxic CVR in healthy tissue (n=10), (2) carbogen cerebral blood flow CVR and blood oxygenation level-dependent CVR in intracranial stenosis patients (n=57), (3) carbogen CVR and clinical measures of disease in patients with asymmetrical intracranial atherosclerotic (n=31) and moyamoya (n=29) disease, and (4) the CVR scan and immediate and longer-term complications (n=92)., Results: Noninvasive blood oxygenation level-dependent carbogen-induced CVR values correlate with (1) lobar hypercarbic normoxic gas stimuli in healthy tissue (R=0.92; P<0.001), (2) carbogen-induced cerebral blood flow CVR in patients with intracranial stenosis (R=0.30-0.33; P<0.012), and (3) angiographic measures of disease severity both in atherosclerotic and moyamoya patients after appropriate processing. No immediate stroke-related complications were reported in response to carbogen administration; longer-term neurological events fell within the range for expected events in this patient population., Conclusions: Carbogen-induced CVR elicited no added adverse events and provided a surrogate marker of cerebrovascular reserve consistent with intracranial vasculopathy., (© 2014 American Heart Association, Inc.)

Background and Purpose: Some studies have reported associations between intracranial atherosclerosis and Alzheimer disease pathology. We aimed to correlate severity of cerebral atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy with neurofibrillary tangles, neuritic plaques, and cerebral infarcts., Methods: This autopsy study (n=163) was drawn from a longitudinal study of subcortical ischemic vascular disease, Alzheimer disease, and normal aging. Multivariable logistic regression models were used to test associations among the 3 forms of cerebrovascular disease and the presence of ischemic and neurodegenerative brain lesions. Apolipoprotein E genotype was included as a covariate in these multivariable models., Results: Cerebral atherosclerosis was positively associated with microinfarcts (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.2-4.4) and cystic infarcts (OR, 2.0; 95% CI, 1.0-4.2) but not Alzheimer disease pathology. Arteriolosclerosis showed a positive correlation with lacunar infarcts (OR, 2.0; 95% CI, 1.0-4.2) but not Alzheimer disease pathology. Cerebral amyloid angiopathy was inversely associated with lacunar infarcts (OR, 0.6; 95% CI, 0.41-1.1), but positively associated with Braak and Braak stage (OR, 1.5; 95% CI, 1.1-2.1) and Consortium to Establish a Registry for Alzheimer Disease plaque score (OR, 1.5; 95% CI, 1.1-2.2)., Conclusions: Microinfarcts, which have been correlated with severity of cognitive impairment, were most strongly associated with atherosclerosis. Possible pathogenetic mechanisms include artery-to-artery emboli, especially microemboli that may include atheroemboli or platelet-fibrin emboli. Arteriolosclerosis was positively, whereas cerebral amyloid angiopathy was negatively correlated with lacunar infarcts, which might prove helpful in clinical differentiation of arteriolosclerotic from cerebral amyloid angiopathy-related vascular brain injury.

Background and Purpose: The aim of this study was to investigate differences in risk factors and stroke mechanisms between intracranial atherosclerosis (ICAS) and extracranial atherosclerosis (ECAS) and between anterior and posterior circulation atherosclerosis., Methods: A multicenter, prospective, Web-based registry was performed on atherosclerotic strokes using diffusionweighted magnetic resonance imaging and magnetic resonance angiography. Stroke mechanisms were categorized as artery-to-artery embolism, in situ thrombo-occlusion, local branch occlusion, or hemodynamic impairment., Results: Onethousand patients were enrolled from 9 university hospitals. Age (odds ratio [OR], 1.033; 95% confidence interval [CI], 1.018-1.049), male gender (OR, 3.399; 95% CI, 2.335-4.949), and hyperlipidemia (OR, 1.502; 95% CI, 1.117-2.018) were factors favoring ECAS (vs ICAS), whereas hypertension (OR, 1.826; 95% CI, 1.274-2.618; P=0.001) and diabetes mellitus (OR, 1.490; 95% CI, 1.105-2.010; P=0.009) were related to posterior (vs anterior) circulation diseases. Metabolic syndrome was a factor related to ICAS (vs ECAS) only in posterior circulation strokes (OR, 2.433; 95% CI, 1.005-5.890; P=0.007). Stroke mechanisms included arterytoartery embolism (59.7%), local branch occlusion (14.9%), in situ thrombo-occlusion (13.7%), hemodynamic impairment (0.9%), and mixed (10.8%). Anterior ICAS was more often associated with artery-to-artery embolism (51.8% vs 34.0%) and less often associated with local branch occlusion (12.3% vs 40.4%) than posterior ICAS (P<0.001)., Conclusions: The prevalence of risk factors and stroke mechanisms differ between ICAS and ECAS, and between anterior and posterior circulation atherosclerosis. Posterior ICAS seems to be closely associated with metabolic derangement and local branch occlusion. Prevention and management strategies may have to consider these differences.

Objective: This study aims to evaluate protective effects of brief repetitive bilateral arm ischemic preconditioning (BAIPC) on stroke recurrence in patients with symptomatic atherosclerotic intracranial arterial stenosis (IAS)., Methods: A total of 68 consecutive cases with symptomatic IAS, diagnosed by imaging, were enrolled in this prospective and randomized study. All patients received standard medical management. Patients in the BAIPC group (n = 38) underwent 5 brief cycles consisting of bilateral upper limb ischemia followed by reperfusion. The BAIPC procedure was performed twice daily over 300 consecutive days. Incidence of recurrent stroke and cerebral perfusion status in BAIPC-treated patients were compared with the untreated control group (n = 30)., Results: In the control group, incidence of recurrent stroke at 90 and 300 days were 23.3% and 26.7%, respectively. In the BAIPC group, incidence of recurrent stroke was reduced to 5% and 7.9% at 90 and 300 days (p < 0.01), respectively. The average time to recovery (modified Rankin Scale score 0-1) was also shortened by BAIPC. Cerebral perfusion status, measured by SPECT and transcranial Doppler sonography, improved remarkably in BAIPC-treated brain than in control (p < 0.01)., Conclusion: This study provides a proof-of-concept that BAIPC may be an effective way to improve cerebral perfusion and reduce recurrent strokes in patients with IAS. Further investigation of this therapeutic approach is warranted as some patients were excluded after randomization.

Purpose of Review: Intracranial atherosclerotic disease (IAD) is likely the most common cause of stroke world-wide and is associated with a very high risk of recurrence. It results in cerebral ischemia due to a variety of mechanisms, including artery-to-artery embolism, hemodynamic failure, and occlusion of penetrating arteries. New imaging modalities focused on physiological consequences of IAD have become available and recent treatment trials have been completed., Recent Findings: We review the traditional imaging modalities, emphasizing the advantages and limitations of each method, and discuss the novel physiological approaches that interrogate physiological process to indicate specific mechanisms of ischemia. These allow deeper understanding of the pathophysiological processes that underlie IAD-related ischemia. The key findings of recent therapeutic trials are reviewed, including the landmark randomized studies showing advantage of antiplatelet agents and risk factor modification, and a significant risk of complications with endovascular approaches., Summary: Current evidence argues for aggressive medical management and suggests caution with interventional treatments. We propose that mechanistic information will further refine the risk assessment of patients with IAD to offer targeted therapy.

Background and Purpose: Although atherosclerotic plaque in the carotid and coronary arteries is accepted as a cause of ischemia, vertebral artery ostium (VAO) atherosclerotic plaque is not widely recognized as a source of ischemic stroke. We seek to demonstrate its implication in some posterior circulation ischemia., Methods: This is a nonrandomized, prospective, single-center registry on consecutive patients presenting with posterior circulation ischemia who underwent VAO stenting for significant atherosclerotic stenosis. Diagnostic evaluation and imaging studies determined the likelihood of this lesion as the symptom source (highly likely, probable, or highly unlikely). Patients were divided into 4 groups in decreasing order of severity of clinical presentation (ischemic stroke, TIA then stroke, TIA, asymptomatic), which were compared with the morphological and hemodynamic characteristics of the VAO plaque. Clinical follow-up 1 year after stenting assessed symptom recurrence., Results: One hundred fourteen patients underwent stenting of 127 lesions; 35% of the lesions were highly likely the source of symptoms, 53% were probable, and 12% were highly unlikely. Clinical presentation correlated directly with plaque irregularity and presence of clot at the VAO, as did bilateral lesions and presence of tandem lesions. Symptom recurrence at 1 year was 2%., Conclusions: Thirty-five percent of the lesions were highly likely the source of the symptoms. A direct relationship between some morphological/hemodynamic characteristics and the severity of clinical presentation was also found. Finally, patients had a very low rate of symptom recurrence after treatment. These 3 observations point strongly to VAO plaque as a potential source of some posterior circulation stroke.

Background and Purpose: The CHADS(2) score is used for risk stratification of ischemic stroke in patients with nonvalvular atrial fibrillation and high CHADS(2) scores are associated with increased risk of stroke. Most components of the CHADS(2) score are also risk factors for atherosclerosis. Therefore, high CHADS(2) scores can be associated with concomitant cerebral atherosclerosis and subsequently atherothrombotic stroke. The aim of this study was to determine whether there are differences in the presence and burden of concomitant cerebral atherosclerosis according to CHADS(2) scores in patients with stroke with nonvalvular atrial fibrillation., Methods: We included 780 consecutive patients with nonvalvular atrial fibrillation who had undergone angiographic studies at index stroke between August 1994 and March 2010 in the present study. We investigated the relationships between the CHADS(2) score and the presence, severity, and pattern of cerebral atherosclerosis and stroke mechanism., Results: Of the 780 patients, concomitant arterial stenosis (≥50%) was found in 231 patients (29.6%). The number of arteries with atherosclerosis increased as the CHADS(2) score increased (P<0.001) as did the proportion of combined extracranial and intracranial atherosclerosis (P<0.001). Multivariate analyses showed that high risk based on the CHADS(2) score was an independent predictor of concomitant cerebral atherosclerosis (OR, 3.121; 95% CI, 1.770 to 5.504) and the presence of proximal stenosis at the symptomatic artery (OR, 3.043; 95% CI, 1.458 to 6.350)., Conclusions: The CHADS(2) score can predict the presence of concomitant cerebral artery atherosclerosis. Increased risk of stroke in patients with high CHADS(2) scores may be partly explained by increased frequency and burden of cerebral atherosclerosis.

Background and Purpose: The relationship between the thickness of the carotid intima (IMT) and brain function remains unclear in those without clinical manifestations of cerebrovascular disease. Understanding the neural correlates of this vascular measure is important in view of emerging evidence linking poorer cognitive performance with increased IMT in individuals without clinical cerebrovascular disease., Methods: Seventy-three participants in the Baltimore Longitudinal Study of Aging (70.9 years; SD, 7.3) were evaluated with carotid artery ultrasound and resting [(15)O]H(2)O positron emission tomography., Results: After adjusting for age, gender, and gray and white matter volumes in the regions where IMT is related to regional cerebral blood flow (rCBF), we found that higher IMT was associated with lower rCBF in lingual, inferior occipital, and superior temporal regions. Higher IMT was also associated with higher rCBF in medial frontal gyrus, putamen, and hippocampal-uncal regions (P=0.001). Whereas women had lower IMT (P=0.01) and mean arterial pressure (P=0.05) than men, they showed more robust associations between IMT and rCBF. The relationship between IMT and rCBF was only minimally affected by additional adjustment for mean arterial pressure., Conclusions: IMT is related to patterns of resting rCBF in older adults without clinical manifestations of cerebrovascular disease, suggesting that there are regional differences in CBF that are associated with subclinical vascular disease.

Background and Purpose: Hemodynamic compromise due to atherosclerotic middle cerebral artery (MCA) disease may induce internal border-zone infarction and cortical neuronal damage. This study aimed to determine whether internal border-zone infarction is associated with increased oxygen extraction fraction (OEF) and a decrease in central benzodiazepine receptors (BZRs) in the overlying cerebral cortex in atherosclerotic MCA disease., Methods: We measured the OEF by using positron emission tomography and (15)O gas in 100 nondisabled patients with atherosclerotic MCA disease in the chronic stage. On MRI, the infarcts were categorized as territorial, border-zone (external or internal), deep perforator, and superior perforator infarcts. In 62 patients, BZRs were measured using (11)C-flumazenil. By using 3-dimensional stereotactic surface projections, the abnormally decreased BZR index ("BZR index") [(the extent of the pixels with Z score more than 2 compared with controls)x(average Z score in those pixels)] was calculated. In the hemisphere affected by MCA disease, the type of infarcts was correlated with the value of OEF or BZR index in the cerebral cortex of the MCA distribution., Results: Compared with patients without internal border-zone infarcts, those with these infarcts (n=18) had significantly increased OEF and significantly high BZR index. Multivariate analysis revealed that internal border-zone infarction was independently associated with increased OEF and high BZR index., Conclusions: In atherosclerotic MCA disease, internal border-zone infarction is associated with increased OEF and a decrease in BZRs in the overlying cerebral cortex, suggesting that hemodynamic compromise may induce internal border-zone infarction and cortical neuronal damage.

Background and Purpose: Whether and how the arterial pathology underlying lacunar ischemic stroke differs from the atherothrombotic processes causing most other ischemic strokes is still debated. Different risks of recurrent stroke and MI after lacunar versus nonlacunar ischemic stroke may support a distinct lacunar arteriopathy., Methods: We prospectively followed a hospital-based cohort of 809 first-ever ischemic stroke patients for 1 to 4 years. We compared risks of death, recurrent stroke, and MI in patients with lacunar versus nonlacunar stroke, and performed an updated meta-analysis of recurrent stroke subtype patterns., Results: During 1725 person-years of follow-up, 109 patients had a recurrent stroke and 31 had MI. All patients at baseline, and 93% with recurrent stroke, had brain imaging and more than half with recurrent stroke had diffusion-weighted MRI. Overall, there was no difference in recurrence risk after lacunar vs nonlacunar stroke, although there was a trend toward a lower recurrence risk in the early weeks after lacunar stroke. Lacunar recurrence was more likely after lacunar than nonlacunar stroke (OR, 6.5; 95% CI, 2.4-17.5; updated meta-analysis OR, 6.8; 95% CI, 4.2-11.2). MI risk was nonsignificantly lower after lacunar than nonlacunar stroke (rate ratio, 0.5; 95% CI, 0.2-1.1; rate ratio after excluding patients with previous ischemic heart disease: 0.3; 95% CI, 0.1-0.9)., Conclusions: Our finding of a trend toward a lower MI risk after lacunar vs nonlacunar stroke and confirmation of both a lower early recurrence risk after lacunar stroke and a tendency of recurrent stroke subtypes to "breed true" support the notion of a distinct nonatherothrombotic lacunar arteriopathy.

Background: There is growing evidence that vascular risk factors (VRF) contribute to cognitive decline. Whether their treatment can slow down the progression of Alzheimer disease (AD) remains unsettled. The aim of this observational study was to evaluate whether the treatment of VRF is associated with a slower cognitive decline in patients who have AD without cerebrovascular disease (CVD)., Methods: We recruited 301 consecutive patients who had AD without CVD (mean age 71.7 years; 69.4% women; first Mini-Mental State Examination [MMSE] mean score 21.6; mean follow-up 2.3 years), who had attended a memory clinic between 1997 and 2003. VRF sought were high blood pressure, dyslipidemia, diabetes mellitus, tobacco smoking, and atherosclerotic disease. Only 21 patients (7.0%) had no VRF. Others were classified as having no VRF treated (n = 72; 25.7%), some VRF treated (n = 119; 42.5%), or all VRF treated (n = 89; 31.8%). We compared MMSE progression over time among these 3 groups using a mixed random effects regression model., Results: Baseline MMSE scores were similar in the 3 groups. With adjustment for confounding factors, MMSE progression over time differed significantly between groups (p = 0.002). Patients with all their VRF treated declined less than those with none of their VRF treated. Those with some VRF treated tended to have an intermediate decline., Conclusions: In patients who have Alzheimer disease without CVD, treatment of vascular risk factors (VRF) is associated with a slower decline in Mini-Mental State Examination score. Randomized controlled trials are needed to confirm this association, but our data suggest that dementia should not prevent treatment of VRF.

Background and Purpose: Unstable atherosclerotic plaques are characterized by increased macrophages and reduced smooth muscle cells (SMCs) and collagen content. Endoglin, an accessory transforming growth factor-beta (TGFbeta) receptor, is a modulator of TGFbeta signaling recently found to be expressed on SMCs in atherosclerotic plaques. Its function in plaque SMCs and plaque development is unknown. Early growth response-1 (EGR-1), a transcription factor downstream of TGFbeta, stimulates SMC proliferation and collagen synthesis. In atherosclerotic lesions, it is mainly expressed by SMCs. Therefore, we studied the TGFbeta, endoglin, and EGR-1 pathway in advanced atherosclerotic plaques in relation to plaque phenotype., Methods: Human carotid atherosclerotic plaques (n=103) were collected from patients undergoing carotid endarterectomy. Histologically, plaques were analyzed for plaque characteristics, ie, collagen, macrophage and SMC content, and intraplaque thrombus. Intraplaque endoglin, pSmad (indicative for TGFbeta signaling), EGR-1, and TGFbeta levels were analyzed using Western blots and enzyme-linked immunosorbent assays, respectively., Results: Higher endoglin and EGR-1 protein levels correlated positively with increased plaque collagen levels, increased smooth muscle cell content, and decreased intraplaque thrombi as well as TGFbeta signaling (pSmad). Although EGR-1 overexpression in vitro stimulated collagen synthesis, inhibiting endoglin resulted in lower EGR-1 levels, decreased SMC proliferation, and decreased collagen content., Conclusions: TGFbeta in human atherosclerotic plaques is active and signals through the TGFbeta/Smad pathway. For the first time, we show a strong association between endoglin and EGR-1, increased collagen and SMCs expression, decreased levels of intraplaque thrombosis, and a stable plaque phenotype.

Background and Purpose: Little is known about the metabolic syndrome (MetS) and the risk of incident stroke. This study is designed to identify particular clusters of MetS components that carry the highest risk of incident stroke., Methods: We analyzed the public use data from the population-based Atherosclerosis Risk in Communities study. At baseline, 14 993 stroke-free middle-aged individuals were followed-up over 9 years for incident stroke. MetS components were defined according to the National Heart, Lung, and Blood Institute/American Heart Association criteria. Incident stroke was identified using a standardized incident events identification and classification protocol. Proportional hazard models were used to assess the RRs and 95% CIs of ischemic stroke associated with MetS and its different clusters., Results: At baseline, the prevalence of MetS was 39%. The mean age was 54, with 26% blacks and 55% females. The hazard ratio of incident ischemic stroke associated with MetS among women (hazard ratio, 2.41; 95% CI, 1.69 to 3.49) and men (hazard ratio, 2.11; 95% CI, 1.56-2.85) was similar. There was a dose-response relationship between the numbers of MetS components and the risk of incidence stroke. Persons with either elevated blood pressure or elevated fasting glucose in the clusters to form a MetS had the highest risk for incident stroke (hazard ratio, 2.74-4.16 comparing to the reference group) than MetS without these 2 components (hazard ratio,

Background and Purpose: Intracranial angioplasty and stenting are therapeutic options for patients with symptomatic intracranial arterial stenoses intractable to medical therapy. However, the long-term safety and clinical efficacy of these techniques are unknown. We sought to assess the long-term outcome and efficacy of these techniques., Methods: Procedural data and 30-day outcomes were collected from patients treated with coronary balloons and stents for >/=70% atherostenoses. Clinical and radiographic follow-up data were obtained at 30 days, 6 months, 12 months, and yearly thereafter., Results: Fifty-three patients (median age, 67 years; interquartile range [IQR], 58.75 to 75 years) with 69 arterial lesions were treated during a 7-year period. The technical success rate was 98.6% (68/69), with a reduction of the median percent stenosis from 85% (IQR, 70% to 95%) to 0% (IQR, 0% to 26%). In 76.8% (53/69) of the procedures, a stent was implanted. The 30-day death/stroke rate was 10.1% (7/69) with 1 death, and within a median follow-up of 24 months (IQR, 10.25 to 36.5 months), the transient ischemic attack or stroke rate reached 5.8% (4/69). Restenosis rate at 1 year was 15.9% (11/69) and was symptomatic in 18.2% (2/11). The restenosis rate was 50% for angioplasty (8/16) and 7.5% (4/53) for stenting (hazard ratio=5.02; 95% CI, 1.22 to 20.68). Factors associated with restenosis were vessel size <2.5 mm (hazard ratio=4.78; 95% CI, 1.35 to 16.93) and interventions performed in the setting of an acute stroke (hazard ratio=6.36; 95% CI, 1.78 to 22.56)., Conclusions: Intracranial stenting may reduce the rate of recurrent ischemia in patients in whom medical therapy is unsuccessful and is probably more durable than angioplasty alone.

Background and Purpose: The molecular pathways involved in the progression of intracranial large artery atherosclerosis (ILA) are largely unknown. Our objective was to prospectively study the relationship between circulating levels of inflammatory markers and fibrinolysis inhibitors, and the risk of progression of symptomatic ILA., Methods: Seventy-five consecutive patients with first-ever symptomatic intracranial atherostenosis were studied. Blood levels of C-reactive protein (CRP), E-selectin, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinases 1, 2, 3, 8, 9, 10, and 13, plasminogen activator inhibitor-1 (PAI-1), and lipoprotein(a) were measured 3 months after the qualifying stroke or transient ischemic attack. Thereafter, patients underwent long-term transcranial Doppler follow-up to detect progression of ILA., Results: During a median follow-up time of 23 months, 25 (33%) patients showed ILA progression. Multivariable adjusted Cox regression models and Kaplan-Meier curves showed that high baseline level of CRP, E-selectin, intercellular adhesion molecule-1, matrix metalloproteinase 9, PAI-1, and lipoprotein(a) predicted ILA progression independently of vascular risk factors. Of them, only CRP (CRP>5.5 mg/L; HR, 5.4 [2.3 to 12.7]; P=0.0001) and PAI-1 (PAI-1>23.1 ng/mL; HR, 2.4 [1.0 to 5.8]; P=0.05) predicted ILA progression also independently of the other studied molecules., Conclusions: Progression of symptomatic ILA is associated with a proinflammatory state, as reflected by high levels of inflammatory markers, and with defective fibrinolysis, as indicated by raised concentrations of endogenous fibrinolysis inhibitors.

Background and Purpose: There are limited data on the prevalence and prognosis of asymptomatic intracranial stenosis (AIS)., Methods: Baseline cerebral angiograms and MR angiograms were used to determine AIS (50% to 99%) coexistent to symptomatic intracranial stenosis for patients enrolled in the Warfarin-Aspirin Symptomatic Intracranial Disease study., Results: Coexisting AIS were detected in 18.9% (n=14/74) of patients undergoing 4-vessel cerebral angiography and 27.3% (n=65/238) of patients undergoing MR angiogram. During a mean follow-up period of 1.8 years, no ischemic strokes were attributable to an AIS on cerebral angiography and 5 ischemic strokes (5.9%, 95% CI: 2.1% to 12.3%) occurred in the AIS territory on MR angiogram (risk at 1 year=3.5%, 95% CI: 0.8% to 9.0%)., Conclusions: Whereas the prevalence of coexisting AIS (50% to 99%) in patients with symptomatic stenosis is high, the risk of stroke from these asymptomatic stenoses is low.

We studied 590 asymptomatic villagers aged > or =40 years in Liangbei County in central rural China and found 41 subjects (prevalence 6.9%) with intracranial atherosclerosis. In a multivariate analysis, the significant risk factors for intracranial stenosis were hypertension (OR 2.53; 95% CI 1.12 to 5.72), glycosuria (OR 3; 1.19 to 7.97), heart disease (OR 4; 1.39 to 11.6), and family history of stroke (OR 5.2; 1.38 to 20). Intracranial atherosclerosis is not uncommon among asymptomatic Chinese subjects.

We used transcranial Doppler to screen 3,057 patients who had at least one vascular risk factor of hypertension, diabetes, or hyperlipidemia and found 385 (12.6%) had middle cerebral artery stenosis. Elderly, hypertension, diabetes, and hyperlipidemia were associated factors. The prevalence escalated quadratically with increasing number of associated factors: from 7.2% for one, to 29.6% for four associated factors. Asymptomatic middle cerebral artery stenosis is common in patients with vascular risk factors.

Background and Purpose: Clinical and imaging studies have reported an independent and intriguing association between intracranial arterial dolichoectasia (IADE) and markers of small-vessel disease (SVD) such as lacune(s). We used a large brain-autopsy collection to investigate the relation between IADE and pathologically assessed cerebral SVD., Methods: The entire arterial tree from the heart to the intracranial small intracerebral arteries was investigated in 381 consecutive autopsies from patients with stroke. Vascular risk factors, heart status (weight, coronary atherosclerosis, and myocardial infarction), prevalence and severity of atherosclerosis from heart to brain (aortic arch, carotid, vertebral, and intracranial arteries), dolichoectasia, cerebral SVD, and brain tissue lesions (lacune(s), état criblé) were evaluated. Analyses were adjusted for age, sex, and heart weight., Results: Twenty-three (6%) of 381 patients had IADE, affecting mainly the basilar artery, with a median basilar artery diameter of 6 mm (range, 4 to 9 mm). Patients with IADE had a >2-fold increase in the prevalence of basilar artery plaques and ulcerated plaques in the aortic arch (both P=0.006), but there were no associations with coronary or cervical artery plaques. SVD was more frequent in IADE-positive than in IADE-negative patients (45% vs 18%; P=0.004). The adjusted odds ratio was 3.85 (95% confidence interval, 1.56 to 9.52). Cerebral amyloid angiopathy was not observed in IADE-positive patients., Conclusions: Compared with stroke patients without IADE, those with IADE were more likely to have pathologic evidence of cerebral SVD and its consequences, independent of age, arterial hypertension, or diabetes mellitus. IADE and cerebral SVD may have unidentified biologic processes in common.

Background and Purpose: This study was to evaluate the retrobulbar hemodynamics in patients who have transient monocular blindness (TMB) without carotid stenosis., Methods: Fifty-nine patients who have TMB without carotid stenosis were studied along with 59 age- and sex-matched controls. Color Doppler-imaging was used to study the retrobulbar hemodynamic by measuring the flow velocities (peak-systolic velocity, and end-diastolic velocity), vascular resistance indices (pulsatility index, and resistance index) in central retinal arteries, short posterior ciliary arteries, and ophthalmic arteries. The patients were divided into 2 groups according to the attack frequency: group 1 (occasional TMB, 2 or fewer attacks, 26 patients) and group 2 (frequent TMB, 3 or more attacks, 33 patients)., Results: The risk factors for atherosclerosis were similar between the cases and controls. The means of end-diastolic velocity were significantly lower in central retinal arteries and ophthalmic arteries, and the pulsatility index and resistance index were significantly higher in all the 3 retrobulbar vessels in TMB patients than for the controls. The differences between patients and controls were greater for the group-2 patients., Conclusions: Patients who have TMB without carotid stenosis had altered retrobulbar hemodynamics with a generalized increase in vascular resistance in the retrobulbar arteries. The role of venous hypertension as an etiology needs further study.

Background and Purpose: The purpose of this study was to clarify the differences in the acute blood pressure course among different ischemic stroke subtypes., Methods: We divided 588 consecutive patients with acute brain infarction into four clinical subgroups to study the blood pressure levels during the initial 6 hospital days., Results: During the 6 days, systolic blood pressure of lacunar and atherothrombotic patients was higher (P=0.0001) and diastolic blood pressure of lacunar patients was higher (P=0.0371) than of patients with the other subtypes. Preexisting hypertension was associated with elevated acute systolic blood pressure in all patients and in each subtype and with elevated acute diastolic blood pressure in all patients, cardioembolic patients, and patients with stroke of other etiology. After adjustment by preexisting hypertension, diabetes mellitus with a hemoglobin A1c >7.0% was associated with elevated systolic blood pressure in all, lacunar, and cardioembolic patients and with diastolic blood pressure in all patients., Conclusions: Blood pressure course of patients sustaining acute stroke varied widely according to stroke subtypes. Poorly controlled diabetes mellitus, as well as preexisting hypertension, appeared to influence blood pressure during the initial week of stroke.

Objective: The ubiquitin-proteasome system is the principal degradation route of intracellular and oxidized proteins, thus regulating many cellular processes conceivably important for atherosclerosis. The aim of this study was to evaluate the activity of ubiquitin-proteasome system in human carotid artery plaques in relation to oxidative stress and clinical manifestation., Methods and Results: In carotid endarterectomy specimens from 83 asymptomatic and 94 symptomatic patients, content of ubiquitin, ubiquitin conjugates, matrix metalloproteases, and NADPH-oxidase-p67 was evaluated by immunoblotting; proteolytic proteasome activity by fluorometric assay; single and double immunostaining for ubiquitin conjugates, 3-nitrotyrosine, apoptosis, smooth muscle alpha-actin, and macrophage CD-68, as well as Sirius Red staining for collagen were performed. Compared with asymptomatic patients, symptomatic patients showed a more unstable plaque phenotype, an increased degree of apoptosis, a significantly higher ubiquitin conjugates content (17.72+/-1.36 versus 10.99+/-1.04; P<0.001), and lower proteasome activity (5.01+/-0.70 versus 9.41+/-1.19 nmol AMC/mg protein/min; P<0.01). Ubiquitin conjugates content was directly correlated to NADPH-p67 and degree of apoptosis. Immunostaining revealed colocalization of ubiquitin conjugates and 3-nitrotyrosine, and accumulation of ubiquitin conjugates in smooth muscle cells and macrophages., Conclusions: In human carotid plaques increased oxidative stress is associated with inhibition of the proteasome activity and accumulation of ubiquitin conjugates, particularly in symptomatic patients. These results suggest a possible role of the ubiquitin-proteasome system in influencing plaque stability.

Objective: The development of a murine model of atherosclerotic plaque rupture., Methods and Results: The left common carotid arteries of male apolipoprotein E (apoE)-deficient mice (9 weeks old) were ligated just proximal to their bifurcations. After 4 weeks on a standard diet, the mice received polyethylene cuff placement just proximal to the ligated site, and the animals were then processed for morphological studies at specific time points. Ligation of the carotid artery in apoE-deficient mice for 4 weeks induced marked intimal hyperplasia, which is a lipid- and collagen-rich lesion that contains a number of macrophages, T lymphocytes, and smooth muscle cells. Subsequently, the cuff placement evoked intraplaque hemorrhage and plaque rupture with fibrin(ogen)-positive luminal thrombus in this region accompanying a decrease in collagen content as well as an increase in apoptotic cells in the intima within a few days after cuff placement., Conclusions: We demonstrated the murine model of human plaque rupture, which is simple, fast, and highly efficient. This model would help us not only to understand the mechanism of human plaque rupture but also to assess various already-known and as-yet-unknown agents in the future.